Dosing
The recommended
dosage
of entecavir is a single 0.5 mg tablet once-daily for chronic hepatitis
B patients beginning treatment for the first time (nucleoside-naïve
patients), and a single 1 mg tablet once-daily for patients
experiencing resistance
to lamivudine.
Entecavir comes in tablet and oral suspension
forms and is taken by mouth without food. The tablets are
film-coated, triangular-shaped and contain 0.5 or 1.0 mg
entecavir. The oral solution contains
0.05 mg/ml entecavir in a 260
ml bottle.
Entecavir should be taken 2 hours after a meal
and 2 hours before the next meal. Based on the pharmacokinetic
profile of entecavir after oral dosing, the estimated apparent volume of distribution
is in excess of total body water, suggesting that entecavir is extensively distributed into tissues.
Pharmacology
Pregnancy
Entecavir is in FDA
Pregnancy Category C. There are no adequate and well-controlled
studies in pregnant women. Reproduction studies have been
performed in rats and rabbits at orally administered doses
of 200 and 16 mg/kg/day and showed no embryo-toxicity or
maternal toxicity in rat and rabbit at doses producing systemic
exposures approximately 28 and 212 times those achieved
at the highest recommended dose of 1 mg/day in humans.
In rats,
maternal toxicity, embryo-fetal toxicity (resorptions),
lower fetal body weights, tail and vertebral malformations,
reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and
ribs were observed at exposures 3,100 times those in humans.
Because
animal reproduction studies are not always predictive of
human response, entecavir should
be used during pregnancy only if clearly needed and after
careful consideration of the risks and benefits. To monitor
fetal outcomes of pregnant women exposed to entecavir,
an Antiretroviral Pregnancy Registry has been established.
Healthcare providers are encouraged to register patients
online at http://www.APRegistry.com
or by calling 1-800-258-4263.
Food and Drug Interactions
Food
Interactions
Oral
administration of entecavir 0.5 mg with a standard high-fat meal (945 kcal,
54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted
in delayed absorption (1.0 to 1.5 hour fed vs. 0.75 hours
fasted), a decrease in Cmax of 44% to 46%, and a decrease in AUC of 18% to 20%. For
this reason, and for best results, it is recommended to
take entecavir 2 hours after a meal and 2 hours
before the next meal.
The
pharmacokinetics of entecavir following a single 1 mg dose were
studied in patients without chronic hepatitis B infection
with selected degrees of renal impairment. Dosage adjustment
is recommended for patients with a creatinine clearance of less than 50 ml/min, including patients
on hemodialysis or continuous
ambulatory peritoneal dialysis (CAPD). Entecavir
should be administered after hemodialysis.
CAPD removed approximately 0.3% of the dose over 7 days.
Drug
Interactions
Coadministration of the HIV nucleoside/tide analogues with entecavir does not appear to reduce the antiviral efficacy
of entecavir against HBV or of
any of these agents against HBV. In HBV combination assays
in vitro, (Ziagen),
(Videx),
(Epivir-HBV), (Zerit), (Viread),
and (Retrovir)
were not antagonistic to the anti-HBV activity of entecavir
over a wide range of concentrations. In HIV antiviral assays,
entecavir was not antagonistic
to the in vitro anti-HIV activity of these NRTIs
at greater than 4 times the Cmax
of entecavir.
Cross
resistance has been observed among HBV nucleoside analogues.
In cell-based assays entecavir had 8- to 30-fold less inhibition of replication
of HBV that contained lamivudine
resistance mutations rtL180M and rtM204V/I than of wild-type
vius.
Important
Safety Information
Lactic
acidosis and severe hepatomegaly with steatosis, including
fatal cases, have been reported with the use of nucleoside
analogues alone or in combination with antiretrovirals.
•
Severe acute exacerbations of hepatitis B
have been reported in patients who have discontinued anti-hepatitis
B therapy, including BARACLUDE. Hepatic function should
be monitored closely with both clinical and laboratory follow-up
for at least several months in patients who discontinue
anti-hepatitis B therapy. If appropriate, initiation of
anti-hepatitis B therapy may be warranted.
•
Limited clinical experience suggests there
is a potential for the development of resistance to HIV
(human immunodeficiency virus) nucleoside reverse transcriptase
inhibitors if BARACLUDE is used to treat chronic hepatitis
B virus infection in patients with HIV infection that is
not being treated. Therapy with BARACLUDE is not recommended
for HIV/HBV co-infected patients who are not also receiving
highly active antiretroviral therapy (HAART). Before initiating
BARACLUDE therapy, HIV antibody testing should be offered
to all patients.
•
BARACLUDE has not been studied as a treatment
for HIV infection and is not recommended for this use.
•
Dosage adjustment of BARACLUDE is recommended
for patients with a creatinine clearance <50 mL/min,
patients with age-related decreases in renal function, and
those on hemodialysis or continuous ambulatory peritoneal
dialysis (CAPD).
•
Since entecavir is primarily eliminated by
the kidneys, coadministration of BARACLUDE with drugs that
reduce renal function or compete for active tubular secretion
may increase serum concentrations of either entecavir or
the coadministered drug.
•
The safety and efficacy of BARACLUDE in liver
transplant recipients are unknown. Renal function must be
carefully monitored both before and during treatment with
BARACLUDE in a liver transplant recipient who has received
or is receiving an immunosuppressant that may affect renal
function, such as cyclosporine or tacrolimus.
•
Patients should be advised that treatment
with BARACLUDE has not been shown to reduce the risk of
transmission of HBV to others through sexual contact or
blood contamination.
•
There are no adequate and well-controlled
studies of BARACLUDE administered to pregnant women. BARACLUDE
should be used during pregnancy only if clearly needed and
after careful consideration of the risks and benefits. There
are no studies on the effect of BARACLUDE on transmission
of HBV from mother to infant. Therefore, appropriate interventions
should be used to prevent neonatal acquisition of HBV. Women
should be instructed not to breast-feed if they are taking
BARACLUDE.
•
Safety and effectiveness of BARACLUDE in pediatric
patients below the age of 16 years have not been established.
The most common adverse events of moderate to severe intensity
among patients treated with BARACLUDE in clinical trials
included: headache (4%), fatigue (3%), diarrhea (1%), and
dyspepsia (1%).
The
recommended dose of BARACLUDE is 0.5 mg once daily in nucleoside-naïve
adults, and 1 mg once daily in lamivudine-refractory adults.
BARACLUDE should be administered on an empty stomach (at
least 2 hours after a meal and at least 2 hours before the
next meal). The optimal duration of treatment with BARACLUDE
for patients with chronic hepatitis B infection and the
relationship between treatment and long-term outcomes such
as cirrhosis and hepatocellular carcinoma are unknown.
Articles on Entecavir (Baraclude)
